X-Message-Number: 25603
Date: Fri, 21 Jan 2005 10:29:41 -0800 (PST)
From: Doug Skrecky <>
Subject: modulating telomeres

[Telomeres shortened by reducing KU86 or DNA-PKcs, but not PARP-1.]

J Cell Biol. 2004 Nov 22;167(4):627-38. Epub 2004 Nov 22
Impact of telomerase ablation on organismal viability, aging, and
tumorigenesis in mice lacking the DNA repair  proteins PARP-1, Ku86, or
DNA-PKcs.
   The DNA repair proteins poly(ADP-ribose) polymerase-1 (PARP-1), Ku86,
and catalytic subunit of DNA-PK (DNA-PKcs) have been involved in telomere
metabolism. To genetically dissect the impact of these activities on
telomere function, as well as organismal cancer and aging, we have
generated mice doubly deficient for both telomerase and any of the
mentioned DNA repair proteins, PARP-1, Ku86, or DNA-PKcs. First, we show
that abrogation of PARP-1 in the absence of telomerase does not affect
the rate of telomere shortening, telomere capping, or organismal
viability compared with single telomerase-deficient controls. Thus, PARP-1
does not have a major role in telomere metabolism, not even in the
context of telomerase deficiency. In contrast, mice doubly deficient for
telomerase and either Ku86 or DNA-PKcs manifest accelerated loss of
organismal viability compared with single telomerase-deficient mice.
Interestingly, this loss of organismal viability correlates with
proliferative defects and age-related pathologies, but not with increased
incidence of cancer. These results support the notion that absence of
telomerase and short telomeres in combination with DNA repair deficiencies
accelerate the aging process without impacting on tumorigenesis.

[Somatostatin boosts KU86.]

Eur J Histochem. 2004 Apr-Jun;48(2):103-10
The expression and the nuclear activity of the caretaker gene ku86 are
modulated by somatostatin.
  Somatostatin is a peptide hormone that exerts antisecretory and
antiproliferative activities on some human tumors. The Ku70/86
heterodimer acts as regulatory subunit of the DNA dependent protein
kinase and its DNA binding activity mediates DNA double strands breaks
repair that is crucial to maintain the genetic integrity of the genome.
The activation of the heterodimer regulates cell cycle progression and
the activity of nuclear transcription factors involved in DNA replication
and cell proliferation. Moreover Ku86 behaves as a receptor for the
growth inhibitory tetradecapeptide, somatostatin. Herein we report that
somatostatin treatment to a colon carcinoma cell line (Caco-2) inhibits
cell growth and, at same time, strongly modulates the activation of
Ku70/86 heterodimer and the levels of Ku86 in the nucleus by increasing
its specific mRNA level. Our findings are consistent with the
hypothesis that somatostatin controls cell cycle progression and DNA
repair through a new signalling pathway that involves the regulation of
Ku86 level and modulates the Ku70/86 activity in the nucleus.

[Leupeptin boosts KU86.]

Mutat Res. 1999 Dec 7;435(3):225-32
Senescent human fibroblasts have elevated Ku86 proteolytic cleavage activity.
  A proteolytic activity capable of cleaving the Ku86 subunit of Ku
protein to two polypeptides, with molecular masses of 69 and 17 kDa in
vitro, is present in a human diploid fibroblast (HDF) cell line. The
activity is elevated in late-passaged and senescent cells, and the
cleaved 69-kDa product seems able to form complex with Ku70 to bind DNA
ends. However, further studies indicate that cleavage of Ku86 could be
inhibited by including leupeptin in the extraction buffer, and no 69 kDa
variant was evident in the cell. In fact, the levels of Ku86, Ku70 and
DNA-end binding activity of Ku remained unchanged during replicative
senescence. Thus, this study reveals an intriguing protease in HDFs,
and also indicates that inconsistent results of Ku86 expression will be
obtained if the protease activity is not completely inhibited.

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